Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

Gerard Minuesa, Steven K. Albanese, Wei Xie, Yaniv Kazansky, Daniel Worroll, Arthur Chow, Alexandra Schurer, Sun-Mi Park, Christina Z. Rotsides, James Taggart, Andrea Rizzi, Levi N. Naden, Timothy Chou, Saroj Gourkanti, Daniel Cappel, Maria C. Passarelli, Lauren Fairchild, Carolina Adura, J. Fraser Glickman, Jessica Schulman, Christopher Famulare, Minal Patel, Joseph K. Eibl, Gregory M. Ross, Shibani Bhattacharya, Derek S. Tan, Christina S. Leslie, Thijs Beuming, Dinshaw J. Patel, Yehuda Goldgur, John D. Chodera and Michael G. Kharas ()
Additional contact information
Gerard Minuesa: Memorial Sloan-Kettering Cancer Center
Steven K. Albanese: Memorial Sloan Kettering Cancer Center
Wei Xie: Memorial Sloan Kettering Cancer Center
Yaniv Kazansky: Rockefeller University and Sloan Kettering Institute
Daniel Worroll: Weill Cornell Graduate School of Medical Sciences
Arthur Chow: Memorial Sloan-Kettering Cancer Center
Alexandra Schurer: Memorial Sloan-Kettering Cancer Center
Sun-Mi Park: Memorial Sloan-Kettering Cancer Center
Christina Z. Rotsides: Memorial Sloan Kettering Cancer Center
James Taggart: Memorial Sloan-Kettering Cancer Center
Andrea Rizzi: Memorial Sloan Kettering Cancer Center
Levi N. Naden: Memorial Sloan Kettering Cancer Center
Timothy Chou: Memorial Sloan-Kettering Cancer Center
Saroj Gourkanti: Memorial Sloan-Kettering Cancer Center
Daniel Cappel: Schrödinger GmbH
Maria C. Passarelli: Memorial Sloan Kettering Cancer Center
Lauren Fairchild: Memorial Sloan Kettering Cancer Center
Carolina Adura: The Rockefeller University
J. Fraser Glickman: The Rockefeller University
Jessica Schulman: Memorial Sloan Kettering Cancer Center
Christopher Famulare: Memorial Sloan Kettering Cancer Center
Minal Patel: Memorial Sloan Kettering Cancer Center
Joseph K. Eibl: Northern Ontario School of Medicine
Gregory M. Ross: Northern Ontario School of Medicine
Shibani Bhattacharya: New York Structural Biology Center, NMR Group
Derek S. Tan: Memorial Sloan Kettering Cancer Center
Christina S. Leslie: Memorial Sloan Kettering Cancer Center
Thijs Beuming: Schrödinger, Inc.
Dinshaw J. Patel: Memorial Sloan Kettering Cancer Center
Yehuda Goldgur: Memorial Sloan Kettering Cancer Center
John D. Chodera: Memorial Sloan Kettering Cancer Center
Michael G. Kharas: Memorial Sloan-Kettering Cancer Center

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08–2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI’s oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

Date: 2019
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DOI: 10.1038/s41467-019-10523-3

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